DESCRIPTION (Applicant's Abstract):The long range goal of this proposal is to develop a better understanding of CNS mechanisms involved in the generation of altered bowel habits and abdominal pain in Irritable Bowel Syndrome (IBS). The current proposal is based on the general hypothesis that these symptoms result from an enhanced responsiveness of central stress circuits, which manifests in altered autonomic responses, and alteration in endogenous pain modulation systems in responses to stressors. The investigator will test the following 3 main hypotheses: 1) lBS patients show enhanced perceptual, attentional, emotional and autonomic responses to acute psychological stress and to learned (conditioned) fear; 2) In response to acute psychological stress and to learned fear, IBS patients, compared to healthy controls, show decreased activation of brain regions which have noradrenergic (NE) innervation and which are part of central stress circuits (incl. amygdala, hippocampus, perigenual cingulate cortex, thalamus and periaqueductal grey); 3) The difference in regional brain activation is related to differences in central NE release between lBS patient and controls. Enhanced regional NE release in lBS patients is related to enhanced responsiveness of ascending NE pathways, which plays a central role in the mediation of responses to stress. We will compare responses of non-constipated lBS patients and healthy controls, using validated measures of autonomic function (skin conductance, heart rate variability, plasma epinephrine), psychophysical measures of viscera sensitivity, and functional brain imaging techniques (H2 150-PET, fMRI and EEG) with different spatial and temporal resolution. We will also test specific hypotheses related to gender differences in central and peripheral responses. In Aim 1, the investigator will characterize the effect of two acute, validated laboratory stressors on perceptual, emotional, autonomic and regional brain responses to rectal distension. In Aim 2, the PI will evaluate the differential effect of conditioned fear to visceral and somatic stimuli on these responses. In Aim 3, the investigator will determine the effect of pharmacologically (yohimbine) induced enhanced central NE release, on regional brain metabolism, cerebral blood glow and electrical response during conditioned fear. The investigator expects that in LBS patients, the greater NE release in response to psychological stressors, learned fear and to yohimbine will be reflected in a biphasic brain activation pattern: An enhanced early response (detected by EEG, and reflecting enhanced activity of arousal systems), and a reduced later response, secondary to postsynaptic inhibition by excessive NE release (detected by fMRI and PET).